Extracorporeal Circulation (ECC) of blood is essential to modern medicine (heart surgery, hemodialysis, plasmapheresis, and life support in intensive care). Systemic anticoagulation is required for ECC, but is the major cause of complications and the limiting factor to the technology. Despite solid understanding of the mechanisms of blood -surface interaction, and despite decades of bioengineering research, the non-thrombogenic prosthetic surface remains an unsolved problem. The problems of thrombosis and anticoagulation increase with time on ECC hence are magnified during prolonged ECC. During the past 30 years our research group and others have developed prolonged extracorporeal life support (, ECLS, ECMO) from bench to animal testing to clinical testing to routine clinical application. Our current grant (and the proposed renewal) is focused on the last major issue limiting prolonged ECC: thrombosis and anticoagulation. We believe we can now solve this problem. The goal of this study is extracorporeal circulation without anticoaqulation. The primary approach is make and evaluate a non-thrombogenic surface which releases nitric oxide at a controlled rate sufficient to prevent platelet adhesion and activation. Our current studies on NO releasing polymers demonstrate that this is feasible. Secondary approaches are 1) to evaluate NO releasing surfaces combined with surface bound heparin; 2) to characterize the physiologic and hematologic responses to extracorporeal circulation without anticoagulation. The results will apply to all blood surface interactions including short term ECC, intravascular and implantable devices and all types of extracorporeal blood processing.